· evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med....

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MAY 2020 • VOL. 12 • NO. 5

ISSN 2072-4209

CONTENTS 61 A New Era of Idiopathic Pulmonary Fibrosis

Management Dr Kwok Yuk Lung (郭旭龍醫生)

65 Oral Targeted Therapy, Can It Be More Durable in the Treatment of Lung Cancer in Asian patients?

Dr Wong King Yan, Matthew (黃敬恩醫生)

68 Updates on the Management of Mild Asthma Dr Wong King Ying (黃琼英醫生)

71 Baloxavir, a New Weapon for an Old Enemy Dr Lo Ho Yin (盧浩然醫生)

Journal of THE SOCIETY OF PHYSICIANS OF HONG KONG

EXECUTIVE COMMITTEE

PRESIDENTDr Lam Tat Chung, Paul 林達聰醫生

VICE PRESIDENTProfessor Tsang Wah Tak, Kenneth曾華德教授

HON. SECRETARYDr Chen Yi Tin 陳以天醫生

HON. TREASURERProfessor Wong Chun Yu, Benjamin 王振宇教授

COMMITTEE MEMBERProfessor Brian Tomlinson 湯寧信教授

CHIEF EDITOR Dr Wong King Yan, Matthew 黃敬恩醫生

EDITORSDr Au Wing Yan區永仁醫生

Professor Chan Hin Lee, Henry 陳衍里教授

Dr Myles Chan 陳普來醫生

Dr Chan Tak Hin 陳德顯醫生

Dr Cheung Ting Kin 張鼎堅醫生

Professor Hung Fan Ngai, Ivan孔繁毅教授

Dr Loo King Fan, Steven 盧景勳醫生

Dr Ma Tin Wei, Ada 馬天慧醫生

Dr Ng Fook Hong 吳福康醫生

Dr Poon Che Mun, Patricia 潘智文醫生

Dr Ting Zhao Wei, Rose丁昭慧醫生

Professor Tse Hung Fat 謝鴻發教授

Professor Wong Chi Sang, Martin 黃至生教授

Dr Yuen Mae Ann, Michele 袁美欣醫生

MAY 2020 Journal of The Society of Physicians of Hong Kong | 61

A New Era of Idiopathic Pulmonary Fibrosis Management

Dr Kwok Yuk Lung (郭旭龍醫生)MBChB, MRCP (UK), FRCP (Edin, Glasg), FHKCP, FHKAM (Medicine)Specialist in Respiratory Medicine

Key words:Idiopathic pulmonary fibrosis (特發性肺纖維化); Pirfenidone (吡非尼酮); Nintedanib (尼達尼布); Antifibrotic (抗纖維化); Tyrosine kinase inhibitor (酪氨酸激酶抑制劑)

I diopathic pulmonary fibrosis (IPF) is a form of interstitial lung disease (ILD) affecting mainly older adults, featur-

ing dyspnoea, chronic dry cough, bilateral Velcro-like crackles, restrictive ventilatory defect, hypoxemia, and characteristic usual interstitial pneumonitis (UIP) pat-tern on both high-resolution computed tomography (HRCT) and lung biopsies. Although IPF accounts for 55% of all ILDs, the aetiology is unknown.1,2 The number of cases has been rising in recent decades, with a prevalence of 494 cases per 100,000 among adults over the age of 65 years in the United States in 2011, which was double the figure observed in 2001.3

IPF is a type of chronic progressive fibrosing interstitial pneumonia. Normal lung tissue is replaced by altered extra-cellular matrix, and the alveolar archi- tecture is destroyed, resulting in decreased lung compliance and impaired

gas exchange. Genetic mutations are found to be associated with an increased IPF risk.3 However, familial IPF with distinct genetic mutations accounts for 1.5–3% of cases only. It is noted that patients with IPF have a much higher bac-terial load in their lungs than those with-out. Understanding the possible role of bacteria in IPF pathogenesis is the focus of the current trial (CleanUP IPF for the Pulmonary Clinical Trials Cooperative).4 Non-genetic risk factors include age, male sex, occupational exposures and cigarette smoking.3,5 Current smokers are generally 13 to 14 years younger at diagnosis compared with non-smokers or former smokers.6

DiagnosisSurgical lung biopsy was once the gold standard for diagnosing IPF. A clinical diagnosis can be established by a con-sistent display of clinical features and UIP patterns on HRCT. The ATS/ERS/JRS/ALAT Clinical Practice Guideline 2018 is commonly adopted as the diagnostic algorithm for IPF (Figure 1).7

Clinical courseThe prognosis of IPF is poor, with most patients dying of respiratory failure within 2.5 to 3.5 years of diagnosis.2 IPF symp-toms precede diagnosis by a median of 1 to 2 years.8 However, the clinical course is highly variable, with some experiencing slow progression and others suffering from acute decompensation and death. Progression can be characterised as sev-eral clinically distinct forms: slow physio-logical deterioration with worsening severity of dyspnoea, rapid deterioration and progression to death, or periods of relative stability alternating with periods of acute respiratory decline in which

patients may require hospitalisation due to respiratory failure.8 Forced vital capa-city (FVC), a measure of lung function, is the key measure of IPF progression.9 The mean annual decline in FVC in patients with IPF is 0.13L to 0.21L, comparing with normal decline of around 0.07L per year in healthy subjects.8,10

Clinical managementThe treatment goals of IPF management are reducing symptoms, preserving lung function, maintaining oxygenation, preventing acute exacerbations, and prolonging survival. Patient education and support, together with pulmonary rehabilitation, should begin at the time of diagnosis and continue throughout the journey of care. Disease progression is monitored by FVC and the 6-minute walk test (6MWT).11 Acute exacerbations can occur at any time and are associated with a 50% mortality rate.12 Preventive care (e.g., vaccinations) should be started early in every patient. Lung transplantation is the best treatment of choice, although it is limited by patient factors and organ supply.

Pharmacological therapies had not been proven to alter the course of the disease or influence mortality, until the recent emergence of evidence showing pirfenidone and nintedanib to be attrac-tive treatment options for IPF patients based on their effectiveness and favour-able safety profile.

PirfenidonePirfenidone is an orally bioavailable anti-fibrotic agent recommended by the ATS/ERS/JRS/ALAT Clinical Practice Guideline for use in patients with IPF.13 Pirfenidone possesses both anti-inflammatory and antifibrotic effects including the

62 | Journal of The Society of Physicians of Hong Kong MAY 2020

Figure 1. Diagnostic algorithm for IPF.7

BAL, bronchoalveolar lavage; HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis; MDD, multidisciplinary discussion; UIP, usual interstitial pneumonitis.

regulation of transforming growth factor β and tumour necrosis factor ɑ, inhibition of fibroblast proliferation and collagen synthesis.14 In the phase III ASCEND trial, the mean decline in FVC in the pirfeni-done group at week 52 was reduced by 45.1% compared with the placebo group. Additionally, death following disease progression occurred less frequently with pirfenidone than placebo.15 Common adverse events (AEs) included nausea, rash, dyspepsia, dizziness and vomiting.16

NintedanibNintedanib is a tyrosine kinase inhibitor approved for the treatment of IPF.13 It tar-gets several growth factor pathways that are involved in the pathogenesis of IPF, including vascular epithelial growth fac-tors 1, 2, and 3, fibroblast growth factor receptors 1, 2, and 3, and platelet-derived growth factor receptor.1

In two replicate 52-week, randomised, double-blind, phase III

trials (INPULSIS-1 and INPULSIS-2), nintedanib-treated IPF was associated with a significant reduction in FVC decline – the difference in annual rate was 93.7 mL to 125.3 mL (Figure 2).17 The effect of nintedanib on the risk of acute exacerbations (events of major clinical signifi-cance in IPF) was not consistent, which might be due to the relative rarity of exacerbations. A meta-analysis of data collected from the phase II TOMORROW trial and phase III INPULSIS-1 and INPULSIS-2 trials found that patients with IPF who were treated with nintedanib had a 47% reduction in acute exacerbations and 30% reduction in all-cause morta-lity. Gastrointestinal events, especially diarrhoea, were the most common AEs and led to treatment discontinuation in about 5% of the patients in this group.18 Dose reduction to 100 mg twice daily can also be considered.19 Other AEs include bronchitis, nasopharyngitis, cough, nausea, and upper respiratory

tract infection. Risks of developing major cardiovascular AEs and myocardial infarc-tion underscore the recognition of cardiac comorbidities in patients with IPF before using nintedanib.20

ConclusionsIPF is a condition with uncertain aetio-logy, pathophysiology, and grave clinical outlook but diagnosis is often delayed. Supportive therapies are essential in clinical management, however, disease progression is inevitable in many patients. Fortunately, a new era of specific pharma-cological treatments targeting IPF has dawned. Both nintedanib and pirfenidone are now recommended as IPF treatment, with the hope of attenuating progression and reducing mortality in what was once a more deadly disease. When selecting between different antifibrotic agents, clinicians should consider patient prefer-ence, tolerance, potential AEs, drug interactions, and comorbid conditions.

Patient suspected to have IPF

Potential cause/associated condition

No

No

Yes

Yes

Further evaluation (including HRCT)

Specific diagnosis

Alternative diagnosis

Not IPF

UIP

IPF

Chest HRCT pattern

MDD

MDD

BAL Surgical lung biopsy

Probable UIP, indeterminate, alternative

diagnosis


References:1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al.

An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.

2. Swigris JJ, Stewart AL, Gould MK, Wilson SR. Patients' perspectives on how idiopathic pulmonary fibrosis affects the quality of their lives. Health Qual Life Outcomes. 2005;3(1):61.

3. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. 2018;378(19):1811-23.

4. CleanUP IPF for the Pulmonary Trials Cooperative. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02759120. Accessed 24 April 2020.

5. Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc 2006;3(4):293-298.

6. Kärkkäinen M, Kettunen HP, Nurmi H, Selander T, Purokivi M, Kaarteenaho R. Effect of smoking and comorbidities on survival in idiopathic pulmonary fibrosis. Respir Res 2017;18(1):160.

7. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-68.

8. Ley B, Collard HR, King Jr TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-40.

9. Karimi-Shah BA, Chowdhury BA. Forced vital capacity in idiopathic pulmonary fibrosis–FDA review of pirfenidone and nintedanib. N Engl J Med 2015;372(13):1189-91.

10. Thomas ET, Guppy M, Straus SE, et al. Rate of normal lung function decline in ageing adults: a systematic review of prospective cohort studies. BMJ Open 2019;9:e028150.

11. Kishaba T. Evaluation and management of idiopathic pulmonary fibrosis [published online March 7, 2019]. Respir Investig doi: 10.1016/j.resinv.2019.02.003.

12. Spagnolo P, Wuyts W. Acute exacerbations of interstitial lung disease: lessons from idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 2017;23(5):411-417.

13. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015;192(2):e3-19.

14. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-9.

15. Nathan SD, Costabel U, Glaspole I, et al. Efficacy of pirfenidone in the context of multiple disease progression events in patients with idiopathic pulmonary fibrosis. Chest 2019;155(4):712-719.

16. King Jr TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-92.

17. Richeldi L, Du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82.

18. Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Bailes Z, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS® trials. Respir Med. 2016;113:74-9.

19. Corte T, Bonella F, Crestani B, Demedts MG, Richeldi L, Coeck C, et al. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res. 2015;16(1):116.

20. Crestani B, Huggins JT, Kaye M, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON. Lancet Respir Med. 2019;7(1):60-68.

Figure 2. Annual rate of decline and change from baseline over time in FVC in INPULSIS-1 and INPULSIS-2.

INPULSIS-1

INPULSIS-2

Adju

sted

Ann

ual R

ate

of C

hang

ein

FVC

(mL/

yr)

Adju

sted

Ann

ual R

ate

of C

hang

ein

FVC

(mL/

yr)

−50

0

−100

−150

−200

−300

−250

−50

0

−100

−150

−200

−300

−250

Difference, 125.3 mL(95% CI, 77.7–172.8)P<0.001

Difference, 93.7 mL(95% CI, 44.8–142.7)P<0.001

Nintedanib,150 mg

Twice Daily(N=309)

Placebo(N=204)

Nintedanib,150 mg

Twice Daily(N=329)

Placebo(N=219)

−114.7

−113.6

−239.9

−207.3

CI, confidence interval; FVC, forced vital capacity

Doctors can request for your personal copy of the Journal.Please send your name and local address to

Dr Lam Tat Chung Paul (林達聰醫生) [email protected]


Oral Targeted Therapy, Can It Be More Durable in the Treatment of Lung Cancer in Asian Patients?

Dr Wong King Yan, Matthew (黃敬恩醫生)MBBS (HK), MRCP (UK), FHKCP, FHKAM (Med)FRCP RCPS (Glasg), FRCP (Edin)Specialist in Respiratory Medicine

Key words:Tyrosine kinase inhibitor (酪氨酸激酶抑制劑); Non-small cell lung cancer (非小細胞肺癌); Osimertinib (奧希替尼); Afatinib (阿法替尼)

O ral tyrosine kinase inhibitors (TKI) have replaced chemotherapy as the first-line treatment in patients

with advanced stage non-small cell lung cancer (NSCLC) harbouring sensitizing epidermal growth factor receptor (EGFR) mutation, given the favourable efficacy and safety profile. Immunotherapies that inhibit PD-1 receptor or PD-L1 used as monotherapy or in combination with che-motherapy in treatment-naïve patients demonstrated longer disease control compared with chemotherapy alone.1,2 Such immunotherapies are considered as first-line treatment for advanced NSCLC when there is an absence of sensitizing EGFR mutation.

Case illustrationA 62-year-old Asian lady was found to

have primary lung tumour (4 cm and a median standardized uptake value [SUV] of 16) at the left lung apex with regional lymph node and spinal metastases in September 2015. Endobronchial ultra-sound guided transbronchial needle aspi-ration (EBUS-TBNA) real-time biopsy of the mediastinal lymph nodes was used to confirm adenocarcinoma originating from the lung with exon 19 deletion. A second generation TKI, afatinib, was commenced as first-line treatment followed by local radiotherapy (RT) targeting the spinal metastasis. After three months of treat-ment, the primary lesion shrank from 4 cm to 2.3 cm and SUV decreased from 16 to 4. Carcinoembryonic antigen (CEA) was reduced from 770 ng/ml to 68 ng/ml. Ablative local RT to the primary lesion was given with minimal side effects. Afatinib was continued for the following 4.5 years. The latest CEA was stabilized at 4.1 ng/ml with no evidence of recur-rence, as confirmed by positron emission tomography (PET) scan. The patient was able to commute frequently to North America before the COVID-19 outbreak.

Not all TKIs are the sameDistinct from the first generation TKIs, second generation TKIs are irreversible, broad-spectrum ErbB receptor family blockers. Afatinib is not involved in the cytochrome P450 metabolic pathway and thus has limited drug-drug interac-tions.3 For patients with lung cancer cells harbouring uncommon G719X and L861Q mutations, afatinib is effective in pro-longing progression-free survival (PFS).4 The third generation TKI osimertinib is highly specific to cancers exhibiting the

EGFR T790M mutation, which is the predominant resistance mechanism in patients after the failure of first- or second-generation TKIs, present in 50–70% of such patients.5 Both second and third generation TKIs can be used in the first-line setting for NSCLC and have demonstrated prolonged PFS compared with first generation TKIs, for example, gefitinib.6,7 Notable grade 3/4 adverse effects observed in patients who received afatinib experienced diarrhoea (13%) and skin rash (9%), while those who received osimertinib experienced diarrhoea (2%) and decreased appetite (2%). Dose reduction of afatinib reduced adverse effects without compromising efficacy.6,7

Can TKIs be more durable in Asian patients?Upfront first-line use of third generation TKIs In the FLAURA trial, the use of the third generation TKI osimertinib in the first-line setting for advanced NSCLC demon-strated improvements in the median overall survival (OS) compared with the first generation TKIs gefitinib and erlotinib (38.6 months vs 31.8 months).7 However, osimertinib conferred no significant survival benefits in Asian patients in the subgroup analysis.7 In patients who progressed on osimertinib, treatment options are limited and most individuals received chemotherapy; this outcome led to clinicians questioning the first-line use of osimertinib in this setting. The financial burden of TKIs should also be considered as the cost of osimertinib is high com-pared with first and second generation therapies. On the other hand, the majority


of patients with acquired resistance to the first-line TKIs erlotinib or gefitinib were found to have T790M mutations,8 sug-gesting the potential utility of osimertinib in this population. As described before, around 60% of patients could be suitable for such sequential treatment; clinical evidence has shown that in patients who progressed on first-line EGFR-TKI therapy and received osimertinib as a salvage therapy, the median PFS during second-line treatment was 10.1 months.9

Sequential TKI treatment, afatinib followed by osimertinibAfatinib, a second generation TKI, was not included in the FLAURA trial. An observational study, GioTag, was con-ducted to look for the sequential use of second- then third- generation TKIs in the real-word setting. Real-world stud-ies include patients with characteristics which might preclude their participation in randomized controlled trials and are designed to explore patient outcomes in populations more representative of clinical practice than prospective clinical trials. Global investigation sites included Asian centres in Singapore, Taiwan and Japan. The overall time on treatment with sequential afatinib and osimertinib was 46.7 months in Asian patients versus 27.6 months in non-Asian patients (Figure).10 Limitations of the GioTag study include its nature as an observational study, absence of a control arm and inclusion of only patients who success-fully switched to salvage treatment with osimertinib. Patients who developed resistance after first line treatment with afatinib through mechanisms other than T790M mutation were also not explored. Further study is required into treatment options following TKI treatment failure. Currently, trials are ongoing to investigate the effectiveness of combining immuno-therapy and chemotherapy.

In conclusion, oral targeted TKI therapy is the standard first-line treatment for advanced NSCLC patients with EGFR

mutations. Third generation TKIs such as osimertinib can be used in the first-line setting or as salvage treatment after fail-ure of a first- or second- generation TKI in patients harbouring the T790M resistant mechanism. First-line use of osimertinib prolonged PFS but did not demonstrate OS benefits in Asian patients. Sequential use of the second generation TKI, afatinib, followed by osimertinib prolonged treat-ment duration, and conferred prolonged periods of chemotherapy-free treatment in Asian patients with acquired T790M resistance. However, larger clinical trials are needed.

References:1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. N Engl J Med.

2016;375(19):1823–1833.2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. N Engl J Med.

2018;378(22):2078–2092.3. GIOTRIF® (afatinib) prescribing information. Hong Kong, Boehringer

Ingelheim, 2019.4. Yang JC, Wu YL, Schuler M, et al. Lancet Oncol. 2015;16(2):141–151. 5. Girard N. Future Oncol. 2018;14(11):1117–1132. 6. Park K, Tan EH, O'Byrne K, et al. Lancet Oncol. 2016;17(5):577–589.7. Ramalingam SS, Vansteenkiste J, Planchard D, et al. N Engl J Med.

2020;382(1):41–50.8. Yu HA, Arcila ME, Rekhtman N, et al. Clin Cancer Res. 2013;19(8):2240–

2247.9. Mok TS, Wu Y-L, Ahn M-J, et al. N Engl J Med. 2017;376(7):629–640.10. Hochmair MJ, Morabito A, Hao D, et al. Future Oncol. 2019;15(25):2905–

2914.11. Yamamoto N, Mera T, Märten A, Hochmair MJ. Adv Ther

2020;37:759–769.12. Hochmair MJ, Morabito A, Hao D, et al. Future Oncol 2018;14:2861–

2874.

Figure: Overall time on treatment with sequential afatinib and osimertinib by subgroup.11,12

CI, confidence interval; NR, not reached.

Time (months)

Trea

tmen

t pro

babi

lity

0.0

0.2

0.4

AsianNon-Asian

0.6

0.8

1.0

Non-Asian(n=138)

Asian(n=50)

Events 2273

27.6(24.5–29.2)

46.7(26.8–NR)

Median time ontreatment, months(90% CI)

0 6 12 18 24 30 36 42 48 54 60

8:10am

7:00am

6:00am

Coffee on the run

Relvar – superior asthma control vs. budesonide/formeterol and other

BD ICS/LABAs in everyday clinical practice*1,2

Long-lasting molecules4,5

Once daily dosing3

Easy to use device6

Asthma control that takes the lead in a 24-hour world

References: 1. Woodcock A, Vestbo J, Bakerly ND, New J, Gibson JM, McCorkindale S, et al. Effectiveness of �uticasone furoate plus vilanterol on asthma control in clinical practice: an open label, parallel-group, randomised controlled trial. Lancet 2017;390:2247–2255. 2. Svedsater H, Jones R, Bosanquet N, Jacques L, Lay-Flurrie J, Leather DA, et al. Patient-reported outcomes with initiation of �uticasone furoate/vilanterol versus continuing usual care in the asthma Salford Lung Study. Respiratory Medicine2018; 141:198–206 3. Relvar (�uticasone furoate/vilanterol) Hong Kong prescribing information (HK032018GDS09v2/EMA201803) 4. Bardsley G, Daley-Yates P, Baines A, Kempsford R, Williams M, Mallon T, et al. Anti-in�ammatory duration of action of�uticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial. Respir Res 2018; 19:133. 5. Braithwaite I, Williams M, Power S, Pilcher J, Weatherall M, Baines A, et al. Randomised, double blind,placebo-controlled, cross-over singledose study of the bronchodilator duration of action of combination �uticasone furoate/vilanterol inhaler in adult asthma. Respir Med 2016; 119:115–121. 6. Svedsater H, Jacques L, Goldfrad C, Bleecker ER. Ease of use of the ELLIPTA dry powder inhaler: datafrom three randomised controlled trials in patients with asthma. Prim Care Respir Med 2014; 24:14019.

Adverse effects observed with Relvar in clinical studies and post-marketing

Frequency Category Number of Subjects Adverse reaction(s)

Very common ≥1/10 Headache, nasopharyngitis

Common ≥1/100 to <1/10 Pharyngitis, rhinitis, candidiasis of mouthand throat, pneumonia, arthralgia, pyrexia

Uncommon ≥1/1,000 to <1/100 ExtrasystolesRare ≥1/10,000 to

<1/1,000Hypersensitivity reactions includinganaphylaxis, angioedema, rash, andurticarial, Palpitations

NAME OF THE PRODUCT RELVAR ELLIPTA QUALITATIVE AND QUANTITIVATIVECOMPOSITION Pre-dispensed dose of 100 mcg or 200mcg of �uticasone furoate and 25mcg vilanterol (as trifenatate). Inhalation powder. INDICATIONS Asthma Relvar Ellipta100/25mcg & 200/25mcg is indicated for the regular treatment of asthma in adults andadolescents aged 12 years and older where use of a combination medicinal product (long-acting beta2-agonist and inhaled corticosteroid) is appropriate: •patients not adequatelycontrolled with inhaled corticosteroids and ‘as needed’ inhaled short acting beta2-agonists.•patients already adequately controlled on both inhaled corticosteroid and long-actingbeta2-agonist. DOSAGE AND ADMINISTRATION Asthma Adults and adolescents aged12 years and over. One inhalation of Relvar Ellipta 100/25mcg or 200/25mcg once daily.Patients usually experience an improvement in lung function within 15 minutes of inhalingRelvar Ellipta. A starting dose of Relvar Ellipta 100/25mcg should be considered for adultsand adolescents 12 years and over who require a low to mid dose of inhaled corticosteroidin combination with a long-acting beta2-agonist. If patients are inadequately controlled onRelvar Ellipta 100/25mcg, the dose can be increased to Relvar Ellipta 200/25mcg, which may provide additional improvement in asthma control. The maximum recommended doseis Relvar Ellipta 200/25mcg once daily. Children aged under 12 years. The safety andef�cacy of Relvar Ellipta in children under 12 years of age has not yet been established in theindication for asthma. Elderly patients (>65 years) & renal impairment No dose adjustment.Relvar Ellipta is for inhalation use only. After inhalation, the patient should rinse their mouthwith water without swallowing. Patients should be made aware that Relvar Ellipta must be used regularly, even when asymptomatic. Patients should be regularly reassessed by ahealthcare professional so that the strength of Relvar Ellipta they are receiving remainsoptimal and is only changed on medical advice. CONTRAINDICATIONS Hypersensitivity to theactive substances or to any of the excipients WARNINGS AND PRECAUTIONS Deteriorationof disease Fluticasone furoate/vilanterol should not be used to treat acute asthma symptomsor an acute exacerbation in COPD, for which a short-acting bronchodilator is required.Increasing use of short-acting bronchodilators to relieve symptoms indicates deteriorationof control and patients should be reviewed by a physician. Patients should not stop therapywith �uticasone furoate/vilanterol in asthma or COPD, without physician supervision sincesymptoms may recur after discontinuation. Asthma-related adverse events and exacerbationsmay occur during treatment with �uticasone furoate/vilanterol. Patients should be asked tocontinue treatment but to seek medical advice if asthma symptoms remain uncontrolled orworsen after initiation of treatment with Relvar Ellipta. Paradoxical bronchospasm Paradoxicalbronchospasm may occur with an immediate increase in wheezing after dosing. This should

be treated immediately with a short-acting inhaled bronchodilator. Relvar Ellipta shouldbe discontinued immediately, the patient assessed and alternative therapy instituted ifnecessary. Cardiovascular effects Cardiovascular effects, such as cardiac arrhythmias e.g.supraventricular tachycardia and extrasystoles may be seen with sympathomimetic medicinalproducts including Relvar Ellipta. Therefore �uticasone furoate/vilanterol should be usedwith caution in patients with severe cardiovascular disease, or heart rhythm abnormalities,thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serumpotassium. Systemic corticosteroid effects Systemic effects may occur with any inhaledcorticosteroid, particularly at high doses prescribed for long periods. These effects are muchless likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’ssyndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density,growth retardation in children and adolescents, cataract and glaucoma and more rarely, arange of psychological or behavioural effects including psychomotor hyperactivity, sleepdisorders, anxiety, depression or aggression (particularly in children). Fluticasone furoate/vilanterol should be administered with caution in patients with pulmonary tuberculosis or inpatients with chronic or untreated infections. The incidence of pneumonia in patients withasthma was common at the higher dose. The incidence of pneumonia in patients with asthmataking Relvar Ellipta 200/25mcg was numerically higher compared with those receivingRelvar Ellipta 100/25mcg or placebo. No risk factors were identi�ed. INTERACTIONSInteraction with beta-blockers Beta2-adrenergic blockers may weaken or antagonise theeffect of beta2-adrenergic agonists. Concurrent use of both non-selective and selectivebeta2-adrenergic blockers should be avoided unless there are compelling reasons for theiruse. Interaction with CYP3A4 inhibitors Caution is advised when co-administering with strongCYP 3A4 inhibitors as there is potential for increased systemic exposure to both �uticasonefuroate and vilanterol. Co-administration should be avoided unless the bene�t outweighsthe increased risk of systemic corticosteroid side effects, in which case patients should bemonitored for systemic corticosteroid side effects. PREGNANCY AND LACTATION PregnancyAdministration of �uticasone furoate/vilanterol to pregnant women should only be considered ifthe expected bene�t to the mother is greater than any possible risk to the foetus. Breast-feedingA decision must be made whether to discontinue breast-feeding or to discontinue �uticasonefuroate/vilanterol therapy taking into account the bene�t of breast-feeding for the childand the bene�t of therapy for the woman. ADVERSE REACTIONS Pneumonia, upperrespiratory tract infection, bronchitis, in�uenza, candidiasis of mouth and throat, headache,extrasystoles, nasopharyngitis, oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough,dysphonia, abdominal pain, arthralgia, back pain, fractures, muscle spasms, pyrexia.

OVERDOSE There is no speci�c treatment for an overdose with �uticasone furoate/vilanterol.If overdose occurs, the patient should be treated supportively with appropriate monitoring asnecessary. Further management should be as clinically indicated or as recommended by thenational poisons centre, where available. Abbreviated Prescribing Information based on RelvarEllipta Hong Kong Prescribing Information HK032018GDS09v2/EMA201803.

Please read the full prescribing information prior to administration.Full prescribing information is available on request from GlaxoSmithKline Ltd, 23/F,

Tower 6, The Gateway, 9 Canton Road, Tsimshatsui, Kowloon, Hong Kong or Avenida InfanteD. Henrique, no.43-53A, Edf. Macau Square 21 andar C, Macau. For adverse events report,

please call GlaxoSmithKline Limited at (852) 9046 2498 or (853) 6366 7071

Safety Pro�le of Relvar Ellipta Inhalation Powder, Pre-dispensed 100 mcg / 25 mcgand 200 mcg / 25 mcg (100/200 mcg �uticasone furoate and 25 mcg vilanterol)

Hypersensitivity to the active substances or to any of the excipients is contraindicated to RelvarRelvar should not be used to treat acute asthma symptoms, for which a short-actingbronchodilator is requiredRelvar should be used with caution in patients with severe cardiovascular disease, pulmonarytuberculosis or in patients with chronic or untreated infectionsSystemic effects may occur with any inhaled corticosteroids, particularly at high dosesprescribed for long periods. Possible systemic effects include Cushing’s syndrome,Cushingoid features, adrenal suppression, growth retardation in children and adolescents and decrease in bone mineral densityPatients should not stop therapy with Relvar in asthma without physician supervision

For Healthcare Professionals only. Images used are for illustrative purposes only.If symptoms arise in the period between doses, an inhaled, short-acting beta

2-agonist should be taken for immediate relief.

PM-HK-FFV-ADVT-190001 (05/2021) Date of preparation: 30/05/2019Relvar Ellipta was developed in collaboration with Trade marks are owned by or licensed to the GSK group of companies. © 2019 GSK group of companies or its licensor.

+25% more patients on Relvar has improved asthma control versus BD ICS/LABAs1

LOC_HK RELVAR PRINT JUN 19 - Relvar Hong Kong 24 hour world 2019_D2.indd 1 04-07-2019 00:53:59

Coffee on the run

Relvar – superior asthma control vs. budesonide/formeterol and other

BD ICS/LABAs in everyday clinical practice*1,2

Long-lasting molecules4,5

Once daily dosing3

Easy to use device6

Asthma control that takes the lead in a 24-hour world

References: 1. Woodcock A, Vestbo J, Bakerly ND, New J, Gibson JM, McCorkindale S, et al. Effectiveness of �uticasone furoate plus vilanterol on asthma control in clinical practice: an open label, parallel-group, randomised controlled trial. Lancet 2017; 390:2247–2255. 2. Svedsater H, Jones R, Bosanquet N, Jacques L, Lay-Flurrie J, Leather DA, et al. Patient-reported outcomes with initiation of �uticasone furoate/vilanterol versus continuing usual care in the asthma Salford Lung Study. Respiratory Medicine 2018; 141:198–206 3. Relvar (�uticasone furoate/vilanterol) Hong Kong prescribing information (HK032018GDS09v2/EMA201803) 4. Bardsley G, Daley-Yates P, Baines A, Kempsford R, Williams M, Mallon T, et al. Anti-in�ammatory duration of action of �uticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial. Respir Res 2018; 19:133. 5. Braithwaite I, Williams M, Power S, Pilcher J, Weatherall M, Baines A, et al. Randomised, double blind,placebo-controlled, cross-over single dose study of the bronchodilator duration of action of combination �uticasone furoate/vilanterol inhaler in adult asthma. Respir Med 2016; 119:115–121. 6. Svedsater H, Jacques L, Goldfrad C, Bleecker ER. Ease of use of the ELLIPTA dry powder inhaler: data from three randomised controlled trials in patients with asthma. Prim Care Respir Med 2014; 24:14019.

Adverse effects observed with Relvar in clinical studies and post-marketing

Frequency Category Number of Subjects Adverse reaction(s)

Very common ≥1/10 Headache, nasopharyngitis

Common ≥1/100 to <1/10 Pharyngitis, rhinitis, candidiasis of mouth and throat, pneumonia, arthralgia, pyrexia

Uncommon ≥1/1,000 to <1/100 Extrasystoles Rare ≥1/10,000 to

<1/1,000Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticarial, Palpitations

NAME OF THE PRODUCT RELVAR ELLIPTA QUALITATIVE AND QUANTITATIVE COMPOSITION Pre-dispensed dose of 100 mcg or 200mcg of �uticasone furoate and 25 mcg vilanterol (as trifenatate). Inhalation powder. INDICATIONS Asthma Relvar Ellipta 100/25mcg & 200/25mcg is indicated for the regular treatment of asthma in adults and adolescents aged 12 years and older where use of a combination medicinal product (long-acting beta2-agonist and inhaled corticosteroid) is appropriate: • patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled short acting beta2-agonists. • patients already adequately controlled on both inhaled corticosteroid and long-acting beta2-agonist. DOSAGE AND ADMINISTRATION Asthma Adults and adolescents aged 12 years and over. One inhalation of Relvar Ellipta 100/25mcg or 200/25mcg once daily. Patients usually experience an improvement in lung function within 15 minutes of inhaling Relvar Ellipta. A starting dose of Relvar Ellipta 100/25mcg should be considered for adults and adolescents 12 years and over who require a low to mid dose of inhaled corticosteroid in combination with a long-acting beta2-agonist. If patients are inadequately controlled on Relvar Ellipta 100/25mcg, the dose can be increased to Relvar Ellipta 200/25mcg, which may provide additional improvement in asthma control. The maximum recommended dose is Relvar Ellipta 200/25mcg once daily. Children aged under 12 years. The safety and ef�cacy of Relvar Ellipta in children under 12 years of age has not yet been established in the indication for asthma. Elderly patients (>65 years) & renal impairment No dose adjustment. Relvar Ellipta is for inhalation use only. After inhalation, the patient should rinse their mouth with water without swallowing. Patients should be made aware that Relvar Ellipta must be used regularly, even when asymptomatic. Patients should be regularly reassessed by a healthcare professional so that the strength of Relvar Ellipta they are receiving remains optimal and is only changed on medical advice. CONTRAINDICATIONS Hypersensitivity to the active substances or to any of the excipients WARNINGS AND PRECAUTIONS Deterioration of disease Fluticasone furoate/vilanterol should not be used to treat acute asthma symptoms or an acute exacerbation in COPD, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician. Patients should not stop therapy with �uticasone furoate/vilanterol in asthma or COPD, without physician supervision since symptoms may recur after discontinuation. Asthma-related adverse events and exacerbations may occur during treatment with �uticasone furoate/vilanterol. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of treatment with Relvar Ellipta. Paradoxical bronchospasm Paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should

be treated immediately with a short-acting inhaled bronchodilator. Relvar Ellipta should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Cardiovascular effects Cardiovascular effects, such as cardiac arrhythmias e.g. supraventricular tachycardia and extrasystoles may be seen with sympathomimetic medicinal products including Relvar Ellipta. Therefore �uticasone furoate/vilanterol should be used with caution in patients with severe cardiovascular disease, or heart rhythm abnormalities, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium. Systemic corticosteroid effects Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Fluticasone furoate/vilanterol should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections. The incidence of pneumonia in patients with asthma was common at the higher dose. The incidence of pneumonia in patients with asthma taking Relvar Ellipta 200/25mcg was numerically higher compared with those receiving Relvar Ellipta 100/25mcg or placebo. No risk factors were identi�ed. INTERACTIONS Interaction with beta-blockers Beta2-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Concurrent use of both non-selective and selective beta2-adrenergic blockers should be avoided unless there are compelling reasons for their use. Interaction with CYP3A4 inhibitors Caution is advised when co-administering with strong CYP 3A4 inhibitors as there is potential for increased systemic exposure to both �uticasone furoate and vilanterol. Co-administration should be avoided unless the bene�t outweighs the increased risk of systemic corticosteroid side effects, in which case patients should be monitored for systemic corticosteroid side effects. PREGNANCY AND LACTATION Pregnancy Administration of �uticasone furoate/vilanterol to pregnant women should only be considered if the expected bene�t to the mother is greater than any possible risk to the foetus. Breast-feeding A decision must be made whether to discontinue breast-feeding or to discontinue �uticasone furoate/vilanterol therapy taking into account the bene�t of breast-feeding for the child and the bene�t of therapy for the woman. ADVERSE REACTIONS Pneumonia, upper respiratory tract infection, bronchitis, in�uenza, candidiasis of mouth and throat, headache, extrasystoles, nasopharyngitis, oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough, dysphonia, abdominal pain, arthralgia, back pain, fractures, muscle spasms, pyrexia.

OVERDOSE There is no speci�c treatment for an overdose with �uticasone furoate/vilanterol. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Further management should be as clinically indicated or as recommended by thenational poisons centre, where available. Abbreviated Prescribing Information based on Relvar Ellipta Hong Kong Prescribing Information HK032018GDS09v2/EMA201803.

Please read the full prescribing information prior to administration.Full prescribing information is available on request from GlaxoSmithKline Ltd, 23/F,

Tower 6, The Gateway, 9 Canton Road, Tsimshatsui, Kowloon, Hong Kong or Avenida Infante D. Henrique, no.43-53A, Edf. Macau Square 21 andar C, Macau. For adverse events report,

please call GlaxoSmithKline Limited at (852) 9046 2498 or (853) 6366 7071

Safety Pro�le of Relvar Ellipta Inhalation Powder, Pre-dispensed 100 mcg / 25 mcg and 200 mcg / 25 mcg (100/200 mcg �uticasone furoate and 25 mcg vilanterol)

Hypersensitivity to the active substances or to any of the excipients is contraindicated to Relvar Relvar should not be used to treat acute asthma symptoms, for which a short-acting bronchodilator is required

Relvar should be used with caution in patients with severe cardiovascular disease, pulmonary tuberculosis or in patients with chronic or untreated infections

Systemic effects may occur with any inhaled corticosteroids, particularly at high doses prescribed for long periods. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents and decrease in bone mineral density

Patients should not stop therapy with Relvar in asthma without physician supervision

For Healthcare Professionals only. Images used are for illustrative purposes only.If symptoms arise in the period between doses, an inhaled, short-acting beta

2-agonist should be taken for immediate relief.

PM-HK-FFV-ADVT-190001 (05/2021) Date of preparation: 30/05/2019Relvar Ellipta was developed in collaboration withTrade marks are owned by or licensed to the GSK group of companies. © 2019 GSK group of companies or its licensor.

+25% more patients on Relvar has improved asthma control versus BD ICS/LABAs1

LOC_HK RELVAR PRINT JUN 19 - Relvar Hong Kong 24 hour world 2019_D2.indd 1 04-07-2019 00:53:59


Updates on the Management of Mild Asthma

Dr Wong King Ying (黃琼英醫生)B.Sc (Hons), MBBS (HK), FHKAM (Medicine), FHKCP, FRCP (EDIN), FRCP(Glasg) Specialist in Respiratory Medicine

Key words:Asthma (哮喘); GINA (全球哮喘防治指引); Short acting beta agonist (SABA) (短效β激動劑); Long acting beta agonist (LABA) (長效β激動劑) ; Inhaled corticosteroids (IC) (吸入性皮質類固醇)

I n 2019, there was a fundamental change in the recommendations for asthma treatment as announced by

the Global Initiatives for Asthma (GINA).1 The GINA 2020 report has just been published and changes are highlighted below.2

(1) Controller therapy is needed for patients with all severity of asthma including the mildest form of intermit-tent asthma. Short acting beta agonists (SABAs), such as salbutamol or terbuta-line alone are no longer recommended to treat adolescents or adults with mild asthma. The overuse of SABAs resulted in excessive asthma deaths in the 1980s in various countries including Australia. Recent studies showed that patients with infrequent symptoms (symptoms occurring less than once per week in the previous 3 months) constituted 30–37%

of adults with acute asthma, 16% of patients with near-fatal asthma and 5–20% of fatal cases.3 As a substantial number of patients with intermittent or mild asthma have severe and life-threat-ening exacerbations, anti-inflammatory therapy, most commonly inhaled corti-costeroids (ICS), is advised to reduce such risks. According to the GINA 2020 report, in patients with mild asthma with symptoms less than twice per month, the preferred initial therapy consists of as-needed ICS-formoterol; another option is low-dose ICS whenever SABA is taken. For patients who show symptoms more than twice per month or demonstrated the need for reliever therapy twice per month, regular low dose ICS with as needed SABA is recommended over as needed ICS-formoterol. A daily leu-kotriene inhibitor such as montelukast is another option but is considered less effective.2

(2) Montelukast is commonly used for mild asthma or allergic rhinitis. The US Food and Drug Administration (FDA) boxed warning in March 2020 mentioned the risks of serious neuropsychiatric events, including suicidality in adults and adolescents, as well as nightmares and behavioural problems in children. Montelukast should not be used to treat allergic rhinitis alone.4

(3) The GINA 2019 report stated that a formoterol-ICS preparation was preferred to SABA for symptomatic relief. Only low dose budesonide/formoterol or beclomethasone/formoterol were recom-mended as reliever therapy. In the 2020 GINA report, ICS-formoterol remains as the preferred reliever for patients as main-tenance and reliever therapy. It is clarified

that for other ICS-LABAs, the reliever is SABA. The maximum recommended dose for budesonide-formoterol in one day is 72 mcg formoterol (12 inhalations of budesonide-formoterol Turbuhaler 200/6 mcg).

Talking about corticosteroids, most local patients refuse to use them due to detrimental side effects, such as osteoporosis and avascular necrosis experienced in severe acute respiratory syndrome (SARS) patients. However, ICS have fewer and less severe side effects than their oral counterparts.

The local side effects of ICS include hoarseness of voice, oropharyngeal candidiasis, cough and throat irritation, and contact hypersensitivity. Those side effects are related to local deposition of ICS and may be attenuated with the use of hydrofluoroalkane (HFA) based metered dose inhalers (MDIs) delivered via a large volume spacer. Myopathy of laryngeal muscle, mucosal irritation and candidiasis may all contribute to hoarse-ness of voice. These effects are usually reversed when treatment is withdrawn.5

Systemic side effects of ICS are of lesser concerns when a low to medium dose is used for mild to moderate asthma. However, there are several factors that may increase such risks. The majority of the ICS dose delivered by MDI or dry powder inhaler (DPI) is deposited in the pharynx and without rinsing, is swallowed and then absorbed from the gastrointes-tinal tract. First pass metabolism primarily by the CYP450 3A4 enzyme subfamily in the liver will convert corticosteroid into its inactive form for excretion. Potent inhi-bitors of CYP450 3A4 (e.g., itraconazole, protease inhibitors, macrolide antibiotics or diltiazem, etc) have the potential to


Figure. Enhanced potency results in a lower daily ICS dose for equivalent efficacy.9

6

5000

500

5

4

3

21

00 500

FLU

FLU

TAA

TAA

BUD

BUD

CIC

CIC

BDP

BDP

FP

FP

MF

MF

FF

Relative GR binding affinity†

Relative GR binding affinity†

GR,

Kd,

nm

ol/L

ICS,

μg/

day

1000 1500 2000 2500 3000 3500

00 500 1000 1500 2000 2500 3000 3500

FF

As ICS potency increases, a lower inhaled dose is required to occupy the same number of GR in the airways, resulting in a lower daily dose for equivalent efficacy

†Potency relative to dexamethasone (dexamethasone = 100)BDP, beclometasone dipropionate; BUD, budesonide; CIC, ciclesonide; FF, fluticasone furoate; FLU, flunisolide; FP, fluticasone proprionate; GR, glucocorticoid receptor; ICS, inhaled corticosteroid; Kd, dissociation constant; MF, mometasone furoate; TAA, triamcinolone acetonide

increase serum level of ICS, in particular, budesonide, ciclesonide and fluticasone.6

The proportion of a dose of ICS reaching the lung varies with different ICS preparations and formula. The cor-ticosteroid enters the lungs and is then absorbed directly into circulation. As there is no first pass effect, the fraction of corticosteroid absorbed from the lung has relatively greater systemic impact. Paradoxically, the systemic effects of ICS may be less detectable in patients with severe asthma because airflow limita-tion inhibits delivery of drugs to the lung periphery.

For MDI HFA preparation of beclo-methasone, fluticasone propionate and ciclesonide, around 60% is delivered to the lungs.7 The budesonide DPI has approximately 15–28% lung deposition while fluticasone propionate DPI has 20%. Current evidence suggests that all low to moderate dose ICS have sufficient therapeutic indices to provide similar efficacy and safety.8 Ciclesonide is a prodrug with low oral bioavailability and a high clearance rate, which can potentially decrease systemic side effects. Amongst different ICS, fluticasone furoate (FF) exhibits the highest binding affinity for the human glucocorticoid receptor, almost 30 times higher than that of dexa-methasone, resulting in low bioavailability from pulmonary absorption. Again, this suggests that the potential systemic side effects of FF would be less common or severe.9 Further testing is needed before these theoretical advantages can be considered clinically important.

The addition of topical gluco- corticoids in ICS-treated patients with

skin lesions will likely increase the sys-temic exposure to steroid. Intermittent use of systemic steroid for asthmatic attacks and low body mass index also increase the risk of systemic steroid side effects. In such patients, it is advisable to monitor for adrenal suppression and skeletal effects such as reduced growth velocity and bone density, osteoporosis and fracture risk with prolonged therapy, and easy bruising.

References:1. Reddel HK, FitzGerald JM, Bateman ED, et al. Eur Respir J 2019;

53(6):1091046.2. Global Initiation for Asthma. 2020 GINA Main Report. Available at:

https://ginasthma.org/gina-reports/. Accessed 23 April 2020.3. Dusser D, Montani D, Chanez P, et al. Allergy 2007;62(6):591–604.4. US Food and Drug Administration. FDA requires Boxed Warning

about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis. Available at: https://www.fda.gov/drugs/fda-requires-boxed-warning-about-serious-mental-health-side-effects-asthma-and-allergy-drug. Accessed 23 April 2020.

5. IJ Williamson, SP Matusiewicz, PH Brown, et al. Eur Respir J 1995; 8(4):590–592.

6. CYP3A and drug interactions. Med Lett Drugs Ther 2005;47(1212):54–55.7. Derendorf H, Nave R, Drollmann A, et al. Eur Respir J 2006;28(5):1042–

1050.8. Kelly HW. Ann Pharmacother 2009;43(3):519–527.9. Daley-Yates PT. Br J Clin Pharmacol 2015;80(3):372–380.

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Baloxavir, a New Weapon for an Old Enemy

Dr Lo Ho Yin (盧浩然醫生)MBBS (HK), MRCP (UK), FRCP (Edin), FHKCP, FHKAM (Medicine)Specialist in Respiratory Medicine

Key words:Baloxavir; Influenza (流感); Treatment (治療); Prophylaxis (預防); Resistance (耐藥)

O ne hundred years ago, the world-wide “Spanish Flu” pandemic infected 500 million people

around the globe and claimed a death toll between 17 and 50 million.1 Another more recent “Swine Flu” pandemic has claimed 0.2–0.3 million lives worldwide in 2009 and 2010.2 Despite the current threat of COVID-19, influenza is definitely one of our oldest enemies with deadli-ness no less than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

In the past decades, adamantanes (e.g., amantadine and rimantadine) and neuraminidase inhibitors (e.g., oseltami-vir, periamivir, zanamivir and laninamivir) have been our only weapons against this foe. However, they are significantly flawed by limited efficacy, especially if given late, and rising resistance. A novel, more effective class of treatment is urgently needed.

A dose of baloxavir shortens flu symptoms to 2.3 days in otherwise healthy patientsBaloxavir is one such new drug that can be used to treat and prevent influenza infections. It is a cap-dependent endo-nuclease inhibitor that blocks viral mRNA transcription and thus inhibits the viral cycle at a very early stage. In its landmark CAPSTONE-1 study, 1,436 patients with influenza (aged 12–64) were given either a dose of baloxavir, a 5-day course of oseltamivir or placebo within 48 hours of symptom onset.3 Baloxavir shortened flu symptoms to about 2.3 days, which is about 24 hours shorter than placebo and comparable to oseltamivir.

Baloxavir improves flu symptoms in 3 days in higher risk patientsIn the CAPSTONE-2 study, 1,163 high-risk patients (39.2% had asthma or chronic lung disease, 27.4% were ≥65 years of age) were given either one dose of baloxavir, or 5-days of oseltamivir or pla-cebo, within 48 hours of symptom onset. Baloxavir improved flu symptoms in 73.2 hours in higher risk patients, again, which is about 24 hours shorter than placebo and is comparable to oseltamivir.

Baloxavir is superior to placebo and oseltamivir in improving symptoms in patients with influenza BSome other interesting findings were brought up by the CAPSTONE-2 study. In patients with influenza B, in whom oseltamivir is well-known to have much weaker action compared with baloxavir, baloxavir out-performed both placebo and oseltamivir, and improved symptoms

about 24 hours faster than either of them (74.6 hours vs 100.6 hours compared with placebo and 101.6 hours compared with oseltamivir).

Baloxavir was also associated with fewer influenza related complications (2.8% vs 10.4%) and lower incidence of secondary bacterial infections requiring antibiotics (3.4% vs 7.5%) compared with placebo. More rapid cessation of viral shedding was also noted with baloxavir (48 hours vs 96 hours for both placebo and oseltamivir arm).

Baloxavir could prevent influenza in household contactsIn the phase III BLOCKSTONE study, a single dose of baloxavir or placebo was given to 752 household contacts of influenza patients. Only 1.9% of these individuals developed influenza infections compared with 13.6% in the placebo arm (86% risk reduction).4

Concerns and future studies of baloxavirOverall, baloxavir is well tolerated. The most notable adverse effect is diarrhoea. About 3% of patients developed diar-rhoea after taking a dose of baloxavir, 1% reported nausea and 1% reported headache.5

Unfortunately, despite all these advantages of baloxavir, treatment-related mutation with the potential to cause drug resistance was noted early; I38x substitution was identified in 9% of treated patients in the CAPSTONE-1 study.5 Such a mutation could potentially render the virus less susceptible to bal-oxavir, however, from the CAPSTONE-1 data, this mutation did not appear to impact the clinical course of influenza. The


Table 1. Prescription information of baloxavir.8

Indication Treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

Dosage Take a single dose of baloxavir orally within 48 hours of symptom onset with or without food. In patients who are:Between 40 kg and 80 kg: A single dose of 40 mgMore than 80 kg: A single dose of 80 mg

Adverse effects Diarrhoea (3%), bronchitis (2%), nasopharyngitis (1%)

Drug Interaction Avoid co-administration with dairy products, calcium-fortified beverages, polyvalent cation-containing drugs laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium or zinc)

Pregnancy No available data

Lactation No data on the presence of baloxavir in human milk

Paediatric patients Safety and effectiveness have not been established in paediatric patients of less than 12 years of age or weighing less than 40 kg

percentage of patients presenting with persistent fever or symptoms on Day 5 was similar among those patients with or without I38X mutation. Nonetheless, treatment-induced mutation and the potential of developing drug resistance is an area of concern regarding baloxavir.

In mouse models, baloxavir given even after 72–96 hours of an infection showed viral inhibition and survival benefits.6,7 However, whether such delayed use in humans is beneficial is still unproven. In addition, laboratory data suggest a synergistic effect between baloxavir and oseltamivir.7 Further stud-ies in these areas are underway and will hopefully allow us to make use of this new molecule in its best way in the near future.

In summary, a single dose of bal-oxavir is a safe and effective way to treat and prevent influenza. Drug resistance is an emerging concern and needs to be looked into in the future.

References:1. Spreeuwenberg P, et al. Am J Epidemiol 2018;187:2561–2567.2. Dawood FS, et al. Lancet Infect Dis 2012;12:687–95.3. Ison MG, et al. Open Forum Infect Dis 2018;5(Suppl 1):S764–S765.4. Ikematsu H, et al. Single-dose baloxavir for the prevention of influenza

among household contacts: a randomized, double-blinded, placebo

controlled post-exposure prophylaxis study (BLOCKSTONE). Abstract #11718. Presented at OPTIONS X 2019. August 28–September 1 2019. Singapore.

5. Hayden FG, et al. N Engl J Med 2018;379:913–923.6. Fukao K, et al. PLoS One 2019;14:e0217307.7. Fukao K, et al. J Antimicrob Chemother 2019;74:654–662.8. Xofluza (baloxavir) [prescribing information]. Hong Kong: Roche.

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